DP IV is a serine protease, which cleaves N-terminal dipeptides from a peptide chain containing, preferably, a proline residue in the penultimate position. Although the biological role of DP IV in mammalian systems has not been completely established, it is believed to play an important role in neuropeptide metabolism, T-cell activation, attachment of cancer cells to the endothelium and the entry of HIV into lymphoid cells.
Likewise, it was discovered that DP IV is responsible for inactivating glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide also known as gastric-inhibitory peptide (GIP). Since GLP-1 is a major stimulator of pancreatic insulin secretion and has direct beneficial effects on glucose disposal, in WO 97/40832 and U.S. Pat. No. 6,303,661 inhibition of DP IV and DP IV-like enzyme activity was shown to represent an attractive approach e.g. for treating type 2 diabetes (also known as non-insulin-dependent diabetes mellitus or NIDDM).
It is known that DP IV inhibitors may be useful for the treatment of impaired glucose tolerance and diabetes mellitus (WO 99/61431; Pederson R A et al, Diabetes 1998 47(8):1253-1258 and Pauly R P et al, Metabolism 1999 48(3):385-389). WO 99/61431 discloses DP IV inhibitors comprising an amino acid residue and a thiazolidine or pyrrolidine group, especially L-threo-isoleucyl thiazolidine, L-allo-isoleucyl thiazolidine, L-threo-isoleucyl pyrrolidine, L-allo-isoleucyl thiazolidine, L-allo-isoleucyl pyrrolidine, and salts thereof. WO 03/72556 discloses DP IV inhibitors comprising a glutaminyl residue and a thiazolidine or pyrrolidine group, especially glutaminyl thiazolidine and glutaminyl pyrrolidine, and salts thereof.
Further examples for low molecular weight DP IV inhibitors are agents such as tetrahydroisoquinolin-3-carboxamide derivatives, N-substituted 2-cyanopyroles and -pyrrolidines, N-(N′-substituted glycyl)-2-cyanopyrrolidines, N-(substituted glycyl)-thiazolidines, N-(substituted glycyl)-4-cyanothiazolidines, boronyl inhibitors and cyclopropyl-fused pyrrolidines. Inhibitors of DP IV are described in U.S. Pat. No. 6,011,155; U.S. Pat. No. 6,107,317; U.S. Pat. No. 6,110,949; U.S. Pat. No. 6,124,305; U.S. Pat. No. 6,172,081; WO 99/61431, WO 99/67278, WO 99/67279, DE 198 34 591, WO 97/40832, DE 196 16 486 C 2, WO 95/15309, WO 98/19998, WO 00/07617, WO 99/38501, WO 99/46272, WO 99/38501, WO 01/68603, WO 01/40180, WO 01/81337, WO 01/81304, WO 01/55105, WO 02/02560, WO 01/34594, WO 02/38541, WO 02/083128, WO 03/072556, WO 03/002593, WO 03/000250, WO 03/000180, WO 03/000181, EP 1 258 476, WO 03/002553, WO 03/002531, WO 03/002530, WO 03/004496, WO 03/004498, WO 03/024942, WO 03/024965, WO 03/033524, WO 03/035057, WO 03/035067, WO 03/037327, WO 03/040174, WO 03/045977, WO 03/055881, WO 03/057144, WO 03/057666, WO 03/068748, WO 03/068757, WO 03/082817, WO 03/101449, WO 03/101958, WO 03/104229, WO 03/74500, WO 04/007446, WO 04/007468, WO 04/018467, WO 04/018468, WO 04/018469, WO 04/026822, WO 04/032836, WO 04/033455, WO 04/037169, WO 04/041795, WO 04/043940, WO 04/048352, WO 04/050022, WO 04/052850, WO 04/058266, WO 04/064778, WO 04/069162, WO 04/071454, WO 04/076433, WO 04/076434, WO 04/087053, WO 04/089362, WO 04/099185, WO 04/103276, WO 04/103993, WO 04/108730, WO 04/110436, WO 04/111041, WO 04/112701, WO 05/000846, WO 05/000848, WO 05/011581, WO 05/016911, WO 05/023762, WO 05/025554, WO 05/026148, WO 05/030751, WO 05/033106, WO 05/037828, WO 05/040095, WO 05/044195, WO 05/047297, WO 05/051950, WO 05/056003, WO 05/056013, WO 05/058849, WO 05/075426, WO 05/082348, WO 05/085246, WO 05/087235, WO 05/095339, WO 05/095343, WO 05/095381, WO 05/108382, WO 05/113510, WO 05/116014, WO 05/116029, WO 05/118555, WO 05/120494, WO 05/121089, WO 05/121131, WO 05/123685 the teachings of which concerning the inhibitors, their production and their use are herein incorporated by reference in their entirety.
There is relatively little in the literature about the use of DP IV-inhibitors for the treatment of neurological diseases. WO 02/34242 and WO 02/34242 disclose the medical use of DP IV-inhibitors for maintenance or potentiation of endogenous neurological and neuropsychological effects of brain neuropeptide Y (NPY) systems via a potentiation of NPY Y1 receptor mediated effects within the central nervous system (CNS).
WO 01/34594 discloses DP IV-inhibitors comprising a proline mimetic, and a method of treating a patient having a disorder selected from the group consisting of strokes, tumors, ischemia, Parkinson's disease, memory loss, hearing loss, vision loss, migraines, brain injury, spinal cord injury, Alzheimer's disease, amyotrophic lateral, multiple sclerosis, diabetic neuropathy and prostate abnormalities.
WO 05/079795 relates to the use of a DP IV inhibitor for the prevention, delay of progression or the treatment of neurodegenerative disorders, cognitive disorders and for improving memory (both short term and long term) and learning ability.
Xu J et al, Bioorg Med Chem Lett 2006, Mar. 1;16(5):1346-9 discloses anti-substituted beta-methylphenylalanine derived amides as potent DP IV-inhibitors with selectivity over both DPP8 and DPP9. These compounds are optimized for the treatment of metabolic disorders and thus are preferably not able to cross the blood brain barrier.
Lankas G R et al, Diabetes 2005 54(10):2988-2994, have tested selective inhibitors of DP IV, DPP8/9 and QPP in 2-week rat toxicity studies and in acute dog tolerability studies. In rats, the DPP8/9 inhibitor produced alopecia, thrombocytopenia, reticulocytopenia, enlarged spleen, multiorgan histopathological changes and mortality. In dogs, the DPP8/9 inhibitor produced gastrointestinal toxicity. The QPP inhibitor produced reticulocytopenia in rats only, and no toxicities were noted in either species for the selective DP IV inhibitor. The DPP8/9 inhibitor was also shown to attenuate T-cell activation in human in vitro models; a selective DP IV inhibitor was inactive in these assays. Moreover, it was found that DP IV inhibitors which were previously reported to be active in models of immune function are more potent inhibitors of DPP8/9. These results suggest that assessment of selectivity of potential clinical candidates may be important to an optimal safety profile for this class of agents.
Definitions:
The following definitions refer to the whole description and especially to the claims.
As used herein, the term “pharmaceutically acceptable” embraces both human and veterinary use: for example the term “pharmaceutically acceptable” embraces a veterinarily acceptable compound or a compound acceptable in human medicine and health care.
Stereoisomers:
All possible stereoisomers of the claimed compounds are included in the present invention. Where the compounds according to this invention have at least one chiral center, they may accordingly exist as enantiomers. Where the compounds possess two or more chiral centers, they may additionally exist as diastereomers. If the formation of an E configuration or, respectively, a Z configuration of a double bond in an “alkenyl group” is possible, both the E and Z configuration are comprised within the scope of the present invention.
It is to be understood that both individual isolated isomers (such as at least 75% pure, in particular at least 90% pure and especially at least 95% pure, for example at least 99% pure) and mixtures of isomers (for example a mixture of all possible isomers, or the two enantiomers of a diastereomer) are encompassed within the scope of the present invention.
Preparation and Isolation of Stereoisomers:
Where the processes for the preparation of the compounds according to the invention give rise to a mixture of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. The compounds may, for example, be resolved into their components enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (−)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l-tartaric acid followed by fractional crystallization and regeneration of the free base. The compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column.
Pharmaceutically Acceptable Salts:
In view of the close relationship between the free compounds and the compounds in the form of their salts, whenever a compound is referred to in this context, a corresponding salt is also intended, provided such is possible or appropriate under the circumstances.
The pharmaceutically acceptable salt generally takes a form in which one or more basic moieties is protonated with an inorganic or organic acid. Representative organic or inorganic acids include hydrochloric, hydrobromic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic, mandelic, methanesulfonic, hydroxyethanesulfonic, benzenesulfonic, oxalic, pamoic, 2-naphthalenesulfonic, p-toulenesulfonic, cyclohexanesulfamic, salicylic, saccharinic or trifluoroacetic acid.
All pharmaceutically acceptable acid addition salt forms of the compounds of the present invention are intended to be embraced by the scope of this invention. Non-pharmaceutically acceptable salts forms of the compounds of the invention may be of use in the preparation of pharmaceutically acceptable salts.
Solvates:
Compounds of the invention may form solvates with water (i.e. hydrate) or common organic solvents which are embraced as an aspect of the invention. Pharmaceutically acceptable solvents (e.g. hydrates) are of particular interest.
Polymorph Crystal Forms:
Furthermore, compounds of the invention (including their salts and solvates) may exist as crystalline solids and all polymorphic forms thereof are included within the scope of the present invention.
Prodrugs:
The present invention further includes within its scope prodrugs of the compounds of this invention. In general, such prodrugs will be functional derivatives of the compounds which are readily convertible in vivo into the desired therapeutically active compound. Thus, in with respect to prodrugs, in the methods of treatment of the present invention, the term “administering” shall encompass the treatment of the various disorders described with prodrug versions of one or more of the claimed compounds of the invention, but which convert to one or more of the compounds of the invention in vivo after administration to the subject.
Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985 and the patent applications DE 198 28 113, DE 198 28 114, WO 99/67228 and WO 99/67279 which are fully incorporated herein by reference.
DP IV-inhibitor
The term “DP IV-inhibitor” or “dipeptidyl peptidase IV inhibitor” is generally known to a person skilled in the art and means enzyme inhibitors, which inhibit the catalytic activity of DP IV.
DP IV-activity
“DP IV-activity” is defined as the catalytic activity of dipeptidyl peptidase IV (DP IV). These enzymes are post-proline (to a lesser extent post-alanine, post-serine or post-glycine) cleaving serine proteases found in various tissues of the body of a mammal including kidney, liver, and intestine, where they remove dipeptides from the N-terminus of biologically active peptides with a high specificity when proline or alanine form the residues that are adjacent to the N-terminal amino acid in their sequence.
DP IV-like Enzymes
Among the rare group of proline-specific proteases, DP IV was originally believed to be the only membrane-bound enzyme specific for proline as the penultimate residue at the amino-terminus of the polypeptide chain. However, other molecules, even structurally non-homologous with the DP IV but bearing corresponding enzyme activity, have been identified recently. DP IV-like enzymes, which are identified so far, are e.g. fibroblast activation protein α, dipeptidyl peptidase IV β, dipeptidyl aminopeptidase-like protein, N-acetylated α-linked acidic dipeptidase, quiescent cell proline dipeptidase, dipeptidyl peptidase II, attractin and dipeptidyl peptidase IV related protein (DPP 8), and are described in the review article by Sedo & Malik (Sedo & Malik, Dipeptidyl peptidase IV-like molecules: homologous proteins or homologous activities? Biochimica et Biophysica Acta 2001 36506: 1-10).
Further DPIV-like enzymes are disclosed in WO 01/19866, WO 02/04610, WO 02/34900 and WO02/31134. WO 01/19866 discloses novel human dipeptidyl aminopeptidase (DPP8) with structural und functional similarities to DPIV and fibroblast activation protein (FAP). WO 02/04610 provides reagents, which regulate human dipeptidyl peptidase IV-like enzyme and reagents which bind to human dipeptidyl peptidase IV-like enzyme gene product. These reagents can play a role in preventing, ameliorating, or correcting dysfunctions or diseases including, but not limited to, tumors and peripheral and central nervous system disorders including pain and neurodegenerative disorders. The dipeptidyl peptidase IV-like enzyme of WO 02/04610 is well known in the art. In the Gene Bank data base, this enzyme is registered as KIAA1492 (registration in February 2001, submitted on Apr. 4, 2000, AB040925).
WO 02/34900 discloses a dipeptidyl peptidase 9 (DPP9) with significant homology with the amino acid sequences of DP IV and DPP8. WO 02/31134 discloses three DP IV-like enzymes, DPRP1, DPRP2 and DPRP3. Sequence analysis revealed, that DPRP1 is identical to DPP8, as disclosed in WO 01/19866, that DPRP2 is identical to DPP9 and that DPRP3 is identical to KIAA1492 as disclosed in WO 02/04610.
Subject
The term “subject” as used herein, refers to an animal, such as a mammal, in particular a human, who has been the object of treatment, observation or experiment.
Therapeutically Effective Amount
The term “therapeutically effective amount” as used herein, means that amount of a compound of the invention compound or pharmaceutical agent that is sufficient to elicit a biological or medicinal response in a tissue system, animal or human, being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated.
Composition
As used herein, the term “composition” is intended to encompass a product comprising the claimed compounds in the therapeutically effective amounts, as well as any product which results, directly or indirectly, from combinations of the claimed compounds.
Co-Administration, Combination
“Co-administration” or “combination” includes administration of a formulation, which includes at least one DP IV-inhibitor of the present invention and at least one further drug agent (for example as listed in the section “Pharmaceutical combinations”) or the essentially simultaneous administration of separate formulations of each agent. The DP IV-inhibitor and the other drug agent may be administered concomitantly or sequentially, as may be required by the appropriate treatment regime, via the same or different routes of administration.
Prevention
The term “prevention” means prophylactic administration of the combination to healthy patients to prevent the outbreak of the conditions mentioned herein. Moreover, the term “prevention” means prophylactic administration of such combination to patients being in a pre-stage of the conditions, to be treated.
Delay
The term “delay of progression” used herein means administration of the combination, such as a combined preparation or pharmaceutical composition, to patients being in a pre-stage of the condition to be treated in which patients a pre-form of the corresponding condition is diagnosed.
Treatment
By the term “treatment” is understood the management and care of a patient for the purpose of combating the disease, condition, or disorder.
Though the causes may differ, patients with neurodegenerative disorders are likely to show localized to generalized atrophy of brain cells leading to compromises in both mental and physical functions.
Dementia
The term “dementia” as used herein includes Alzheimer type dementia, Parkinson type dementia, Huntington type dementia, Pick's type dementia, Creutzfeldt-Jakob type dementia, senile dementia, pre-senile dementia, idiopathic-related dementia, trauma-related dementia, stroke-related dementia, cranial bleed-related dementia, vascular dementia, and includes acute, chronic or recurring forms.
Chemical Definitions
Throughout the description and the claims the expression “alkyl”, unless specifically limited, denotes a C1-12 alkyl group, such as a C1-6 alkyl group (for example a C1-4 alkyl group). Alkyl groups may be straight chain or branched. Suitable alkyl groups include, for example, methyl, ethyl, propyl (e.g. n-propyl and isopropyl), butyl (e.g. n-butyl, tert-butyl and sec-butyl), pentyl (e.g. n-pentyl, hexyl (e.g. n-hexyl heptyl (e.g. n-heptyl) and octyl (e.g. n-octyl).
Other suitable alkyl groups include 1-ethyl-propyl, 3-methyl-butyl and 2,2-dimethyl-propyl), and 3,3-dimethyl-butyl), nonyl (e.g. n-nonyl and 7-methyl-octyl) and decyl (e.g. n-decyl), in particular methyl and ethyl. Further suitable alkyl groups include isobutyl.
“Lower alkyl” refers to an alkyl group having 1-4 carbon atoms e.g. methyl or ethyl.
The expression “alk”, for example in the expression “alkoxy”, should be interpreted in accordance with the definition of “alkyl”.
Exemplary alkoxy groups include methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy and octyloxy. Other examples include nonyloxy and decyloxy. Further examples include n-propoxy, n-butoxy, n-pentoxy, n-hexoxy, n-heptoxy and n-octoxy).
The expression “alk”, in the expression “thioalkyl” should be interpreted in accordance with the definition of “alkyl”. Exemplary thioalkyl groups include methylthio-.
The expression “alkan”, for example in the expression “alkanoyl” should be interpreted in accordance with the definition of “alkyl”. Exemplary alkanoyl (i.e. acyl groups) include ethanoyl (i.e. acetyl), propionyl and butyryl.
The expression “acyl”, unless specifically limited, denotes a C1-12acyl residue, such as a C1-8acyl residue e.g. a C1-6 acyl residue and in particular a C1-4acyl residue. Examples of acyl include the alkanoyl groups mentioned previously.
The expression “alk” in the expressions “haloalkyl” and “haloalkoxy” should be interpreted in accordance with the definition of “alkyl”. For instance, by the term “C1-6haloalkyl” is meant a C1-6alkyl group which is substituted by at least one halo atom (for example fluoro, chloro or bromo). C1-6fluoroalkyl represents a C1-6alkyl group (such as those specifically recited above) which is substituted by at least one fluoro atom, including for example, fluoromethyl, difluoromethyl and trifluoromethyl (in particular trifluoromethyl). The expressions C1-6haloalkoxy and C1-6fluoroalkoxy can be interpreted accordingly.
The expression “alkenyl”, unless specifically limited, denotes a C2-12alkenyl group, such as a C2-6alkenyl group (for example a C2-4alkenyl group), which contains at least one double bond at any desired location and which does not contain any triple bonds. Alkenyl groups may be straight chain or branched. Exemplary alkenyl groups include propenyl, butenyl. Other examples include ethenyl, pentenyl and hexenyl. Exemplary alkenyl groups including two double bonds include pentadienyl, e.g. (1E, 3E)-pentadienyl.
The expression “alkynyl”, unless specifically limited, denotes a C2-12 alkynyl group, such as a C2-6alkynyl group (for example a C2-4alkynyl group), which contains at least one triple bond at any desired location. Alkynyl groups may be straight chain or branched. Exemplary alkynyl groups include ethynyl, propynyl and butynyl. Further examples include ethynyl, pentynyl and hexynyl.
Generally, the term “alkynyl group” comprises also compounds having double bonds as well as triple bonds, i.e. “alkeninyl groups”, for example having one double bond and additionally, one triple bond. As an example therefore, the group 4,7-dimethyl-oct-6-en-2-in-1-yl (i.e. —CH2—C≡C—CH(CH3)—CH2—CH═C(CH3)2) may be given.
The expression “amino” means a primary, secondary or tertiary amine group. Suitably amino is represented by formula —NRaRb wherein Ra and Rb are selected from hydrogen or alkyl (e.g. C1-4alkyl) or Ra and Rb may be joined to form a 4-7 membered ring optionally containing a further N or O atom. Examples of amino include NH2, NHMe, NMe2, NHEt, NEt2, NMeEt, azetidine, pyrrolidine, piperidine, morpholine, piperazine and N-methylpiperazine.
The expression “amine”, unless qualified as “secondary amine” or “tertiary amine” means NH2.
Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
The expression “carbocycle”, unless specifically limited, denotes any ring system in which all the ring atoms are carbon and which typically contain between three and twelve ring carbon atoms, suitably between three and ten carbon atoms and more suitably between three and eight carbon atoms. Carbocycle groups may be saturated or partially unsaturated, but do not include aromatic rings. Examples of carbocycle groups include monocyclic, bicyclic, and tricyclic ring systems, in particular monocyclic and bicyclic ring systems. Other carbocylcyl groups include bridged ring systems (e.g. bicyclo[2.2.1]heptenyl). A specific example of a carbocycle group is a cycloalkyl group. A further example of a carbocycle group is a cycloalkenyl group. A further example of a carbocycle group is a cycloalkynyl group.
The term “cycloalkyl”, unless specifically limited, denotes a C3-12cycloalkyl group, such as a C3-10cycloalkyl (for example a C3-8 cycloalkyl group). Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. A most suitable number of ring carbon atoms is three to six. The term “cycloalkenyl”, unless specifically limited, denotes a C5-12cycloalkenyl group, for example a C5-10cycloalkenyl group such as a C5-8cycloalkenyl (for example a C6-8 cycloalkenyl group or a C5-6 cycloalkenyl group). A specific example is cyclohexenyl. Further specific examples include cyclopropenyl, cycloheptenyl and cyclooctenyl. A most suitable number of ring carbon atoms is five to six.
Other exemplary carbocycle groups include bridged ring systems (e.g. bicyclo[2.2.1]heptanyl bicyclo[2.2.1]heptenyl and adamantane, which are considered to be examples of cycloalkenyl and cycloalkyl groups respectively).
By the term “C3-6cycloalkylimine” is meant C3-6cycloalkyl group in which one of the ring carbon atoms is replaced by a nitrogen atom. Exemplary C3-6cycloalkylimine groups include azetidine (also known as trimethylene imine, which may be 1-azetidine, 2-azetidine or 3-azetidine, in particular 3-azetidine), pyrrolidine (including pyrrolidin-1-yl, pyrrolidin-2-yl and pyrrolidin-3-yl) and piperidine (including piperidin-1-yl, piperidin-2-yl, piperidin-3-yl and piperidin-4-yl).
The expression “heterocyclic” or “heterocycle”, unless specifically limited, denotes a carbocyclic residue (for example a cycloalkyl group, e.g. cyclopentyl or more particularly cyclohexyl), wherein one or more (e.g. 1, 2, 3 or 4, such as 1, 2 or 3, in particular 1 or 2, especially 1) ring atoms are replaced by heteroatoms selected from N, S or O. By the term “C3-12heterocycle” is meant a C3-12carbocyclyl group in which at least one of the ring carbon atoms is replaced by a heteroatom. A heterocyclic group could therefore be monocylic or could alternatively be bicyclic. More usually it will be monocyclic. Exemplary heterocyclic groups containing one hetero atom include: three membered rings (e.g. oxirane aziridine, thiirane); four membered rings (e.g. oxetane, azetidine, thietane); five membered rings (e.g. pyrrolidine and tetrahydrofuran, but also pyrroline and tetrahydrothiophene); and six membered rings (e.g. piperidine or tetrahydropyran). Exemplary heterocyclic groups containing two hetero atoms include five membered rings (e.g. pyrazoline, imidazoline, pyrazolidine, imidazolidine, dioxolane, thiazolidine, oxazolidine); and six membered rings (e.g. morpholine and piperazine but also dioxane). A further specific example of a heterocycle group is a cycloalkenyl group (e.g. a cyclohexenyl group) wherein one or more (e.g. 1, 2 or 3, particularly 1 or 2, especially 1) ring atoms are replaced by heteroatoms selected from N, S and O. An example of such a group is dihydropyranyl (e.g. 3,4-dihydro-2H-pyran-2-yl-).
An example of a bridged heterocyclic group is utropine.
The expression “aryl”, unless specifically limited, denotes a C6-12 aryl group, suitably a C6-10 aryl group, more suitably a C6-8 aryl group. Aryl groups will contain at least one aromatic ring (e.g. one, two or three rings), but may also comprise partially or fully unsaturated rings. An example of a typical aryl group with one aromatic ring is phenyl. Examples of aromatic groups with two aromatic rings include naphthyl. Examples of naphthyl include naphth-1-yl- and naphth-2-yl-. Examples of aryl groups which contain partially or fully unsaturated rings include pentalene, indene and indane. Other aryl groups include tricyclic rings such as anthracene.
The expression “heteroaryl”, unless specifically limited, denotes as an aryl residue, wherein one or more (e.g. 1, 2, 3, or 4, such as 1, 2 or 3) ring atoms are replaced by heteroatoms selected from N, S and O or else a 5-membered aromatic ring containing one or more (e.g. 1, 2, 3, or 4, such as 1, 2 or 3) ring atoms selected from N, S and O. Exemplary monocyclic heteroaryl groups having one heteroatom include: five membered rings (e.g. pyrrole, furan, thiophene); and six membered rings (e.g. pyridine, such as pyridin-2-yl, pyridin-3-yl and pyridin-4-yl). Exemplary monocyclic heteroaryl groups having two heteroatoms include: five membered rings (e.g. pyrazole (e.g. pyrazol-3-yl), oxazole, isooxazole, thiazole, isothiazole, imidazole, such as imidazol-1-yl, imidazol-2-yl imidazol-4-yl); six membered rings (e.g. pyridazine, pyrimidine, pyrazine). Exemplary monocyclic heteroaryl groups having three heteroatoms include: triazole e.g. 1,2,3-triazole and 1,2,4-triazole. Exemplary monocyclic heteroaryl groups having four heteroatoms include tetrazole.
Exemplary bicyclic heteroaryl groups include quinoline, benzothiophene, indazole, indole and purine. Exemplary bicyclic heteroaryl groups also include isoquinoline, quinolizine, benzodioxolane, benzodioxane, benzodioxepine (e.g. indol-6-yl), indoline, benzimidazole Further examples of bicyclic heteroaryl groups include (e.g. 1H-indol-6-yl), benzimidazole, chromene, benzodioxolane, benzodioxane (e.g. 2,3-dihydro-benzo[1,4]dioxin-6-yl) and benzodioxepine.
Exemplary tricyclic heteroaryl groups include carbazole and acridine groups.
The expression “-alkylaryl”, unless specifically limited, denotes an aryl residue which is connected via an alkylene moiety such as a C1-6alkylene moiety e.g. a C1-4alkylene moiety. Examples of -alkylaryl include: -methylaryl and -ethylaryl (e.g. 1-arylethyl- or 2-arylethyl-); or phenylalkyl-, which may be optionally substituted. Specific examples of -alkylaryl functions include: phenylmethyl- (i.e. benzyl), phenylethyl- (e.g. 2-phenyleth-1-yl or 1-phenyl-eth-1-yl), p-tolyl-methyl-, (p-tolyl)-ethyl-, (m-tolyl)-methyl-, (m-tolyl)-ethyl-, (o-tolyl)-methyl-, (o-tolyl)-ethyl-, 2-(4-ethyl-phenyl)-eth-1-yl-, (2,3-dimethyl-phenyl)-methyl-, (2,4-dimethyl-phenyl)-methyl-, (2,5-dimethyl-phenyl)-methyl-, (2,6-dimethyl-phenyl)-methyl-, (3,4-dimethyl-phenyl)-methyl-, (3,5-dimethyl-phenyl)-methyl-, (2,4,6-trimethyl-phenyl)-methyl-, (2,3-dimethyl-phenyl)-ethyl-, (2,4-dimethyl-phenyl)-ethyl-, (2,5-dimethyl-phenyl)-ethyl-, (2,6-dimethyl-phenyl)-ethyl-, (3,4-dimethyl-phenyl)-ethyl-, (3,5-dimethyl-phenyl)-ethyl-, (2,4,6-trimethyl-phenyl)-ethyl-, (2-ethyl-phenyl)-methyl-, (3-ethyl-phenyl)-methyl-, (4-ethyl-phenyl)-methyl-, (2-ethyl-phenyl)-ethyl-, (3-ethyl-phenyl)-ethyl-, (4-ethyl-phenyl)-ethyl-, 2-fluoro-benzyl, (1-methyl-2-fluoro-phen-6-yl)-methyl-, (1-methyl-2-fluoro-phen-4-yl)-methyl-, (1-methyl-2-fluoro-phen-6-yl)-ethyl-, (1-methyl-2-fluoro-phen-4-yl)-ethyl-, 1H-indenyl-methyl-, 2H-indenyl-methyl-, 1H-indenyl-ethyl-, 2H-indenyl-ethyl-, indanyl-methyl-, indan-1-on-2-yl-methyl-, indan-1-on-2-yl-ethyl-, tetralinyl-methyl-, tetralinyl-ethyl-, fluorenyl-methyl-, fluorenyl-ethyl-, dihydronaphthalinyl-methyl-, dihydronaphthalinyl-ethyl-, or (4-cyclohexyl)-phenyl-methyl-, (4-cyclohexyl)-phenyl-ethyl-.
The expression “-alkylheteroaryl”, unless specifically limited, denotes a heteroaryl residue which is connected via an alkylene moiety such as a C1-6alkylene moiety e.g. a C1-4alkylene moiety. Examples of -alkylheteroaryl include -methylheteroaryl and -ethylheteroaryl (e.g. 1-heteroarylethyl- and 2-heteroarylethyl-). Specific examples of -alkylheteroaryl groups include pyridinylmethyl-, N-methyl-pyrrol-2-methyl-N-methyl-pyrrol-2-ethyl-, N-methyl-pyrrol-3-methyl-, N-methyl-pyrrol-3-ethyl-, 2-methyl-pyrrol-1-methyl-, 2-methyl-pyrrol-1-ethyl-, 3-methyl-pyrrol-1-methyl-, 3-methyl-pyrrol-1-ethyl-, 4-pyridino-methyl-, 4-pyridino-ethyl-, 2-(thiazol-2-yl)-ethyl-, 2-ethyl-indol-1-methyl-, 2-ethyl-indol-1-ethyl-, 3-ethyl-indol-1-methyl-, 3-ethyl-indol-1-ethyl-, 4-methyl-pyridin-2-methyl-, 4-methyl-pyridin-2-yl-ethyl-, 4-methyl-pyridin-3-methyl-, 4-methyl-pyridin-3-ethyl-.
The terms “halogen” and “halo” include fluorine, chlorine, bromine and iodine, especially fluorine, chlorine and bromine, in particular fluorine and chlorine (e.g. fluorine).